原沉默子及染色质重构蛋白对基因沉默和异染色质结构的作用
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摘要
酿酒酵母染色质的大部分端粒附近,rDNA区域以及HML和HMR区域基因是沉默不表达的,形成了类似高等真核生物的异染色质结构。沉默子HML-E和HML-I对其第三号染色质的HML区域基因沉默起着决定作用,它们由复制起点识别复合物(Origin Recognition Complex, ORC)结合位点, (repressor activator Protein, Raplp)结合位点和自主复制序列(autonomously replicating sequence binding factor, Ab.f1p)结合位点中的三个或者两个结合位点所组成,这些结合位点被称为原沉默子(protosilencer)。沉默子通过多种蛋白募集沉默信息(silent information regulator, Sir)蛋白到它上面,进而沿着染色质纤维传递,形成基因沉默的异染色质区域。但组成沉默子的原沉默子单独情况下对基因沉默的作用尚未研究清楚,此外常染色质与异染色质之间的转化需要染色质的重构,但任意一种Sir蛋白都没有染色质重构活性,而染色质重构因子例如Fun30, Snf2, IswI等对基因沉默起一定作用,但是染色质重构因子在基因沉默以及异染色质形成过程中的具体作用尚未研究清楚。
为研究原沉默子对基因沉默的作用,本研究采用带有报告基因URA3的不同原沉默子替代HML区域HML-I沉默子,比较URA3的基因表达的差别,发现原沉默子单独情况下没有沉默作用,但与HML-E沉默子共同作用下能在两者之间形成一定的基因沉默；为研究原沉默子拷贝数对基因沉默的影响,本研究利用带有报告基因URA3的不同拷贝数的原沉默子Abflp结合位点替代HML-I沉默子,发现增加拷贝数能增强基因沉默作用；为研究原沉默子在不同位置对基因沉默的影响,本研究利用带有报告基因URA3的原沉默子Raplp结合位点在不同位置的序列替代HML-I沉默子,发现Raplp在本身原来的位置有一定的基因沉默作用,在其他位置基本没有基因沉默作用。为研究原沉默子基因沉默产生差异的原因,通过DNA拓扑结构法研究了不同条件下原沉默子对该区域染色质DNA螺旋程度产生的影响,发现发现负超螺旋DNA的比例Abflp结合位点最高,ORC次之,Rap1结合位点最弱；为研究它们对对染色质结构产生的影响,通过不完全MNase降解结合Southern blot法发现不同的原沉默子与沉默子相互作用下原沉默子附近的核小体结构发生较大变化,但沉默子附近的染色质结构没有发生变化,通过染色质结构变化上不同推测,可能是沉默子与原沉默子之间相互作用会随着它们种类,数目,位置的不同而不同,从而导致形成的基因沉默上存在差别。
为研究重构蛋白在异染色质重排中的具体作用,本研究敲除了酵母的IswIp, Isw2p, Chdlp, Ino80p, Rad54p, Fun30等基因。发现敲除Isw2p, Chdlp, Ino80p, Rad54p基因对酵母的基因沉默没有影响,而敲除IswIp, Fun30基因会酵母的基因沉默产生影响；通过拓扑结构法以及MNase不完全降解结合Southern blot法发现敲除Fun30对异染色质的形成影响很大而对异染色质的维持影响不大,而敲除IswI对异染色质的形成影响不大但对异染色质的稳定维持影响很大。
本研究创新之处：1)不同的原沉默子对插入的外源基因有不同的沉默作用,对异染色质核小体的排列以及染色质DNA螺旋有不同的影响；2)增加原沉默子Abfl结合位点拷贝数能增强基因沉默作用：3)改变原沉默子的排列也会影响基因沉默；4)染色质重构因子Fun30和IswI这两种蛋白对基因沉默起增强作用；5)Fun30对异染色质的形成起重要作用而对异染色质的稳定维持起很小作用,而IswI对异染色质的形成起很小作用,而对异染色质的稳定维持起重要作用。
The basic unit of chromatin is the nucleosome, which is composed of two copies each of the four core histones H2A.H2B, H32. H42 and approximately 146 bp of DNA wrapped in about two turns around a histone octamer complex. Chromatin is divided into different regions, which are loosely structured euchromatin and highly condensed chromatin heterochromatin. Gene expression is normal in euchromatin,but gene expression is silent in heterochromatin which is also known as silent chromatin. Heterochromatin in Saccharomyces cerevisiae exists at HML and HMR loci as well as subtelomeric region. Like its metazoan counterpart, Saccharomyces cerevisiae heterochromatin consists of highly like its metazoan counterpart, its heterochromatin consists of highly ordered and stably positioned nucleosomes. It also bears characteristic histone modifications such as hypoacetylation and hypomethylation, DNA replication occurs in later S phase.
Establishment of HM loci silencing is initiated at silencer, which are composed of two or three combinations of binding sites for proteins Rap1 protein, Abf1 protein, and the ORC. These binding sites are called protosilencer. It was proposed that silencer-binding proteins recruit a complex of SIR complex (Sir2p/Sir3p/Sir4p), which is an integral part of the silent chromatin. Sir2p was found to be a histone deacetylase, Sir3p/Sir4p interact with the N-terminal tails of histones H3 and H4, and there is evidence that Sir3p (hence the SIR complex) has a much higher affinity for hypoaceylated histones. So Sir2p recruited to the silencer deacetylates histones in an adjacent nucleosome enabling it to bind another SIR complex with high affinity, the nucleosome-bound SIR complex in turn deacetylates the neighboring nucleosome allowing it to recruit a new SIR complex,In this manner, the SIR complex promotes its own propagation along the chromatin to form heterochromatin.
Although S. cerevisiae silencers function through a common mechanism, they exhibit different efficiencies in gene silencing. At the HMR locus, HMR-E can silence the HMRa genes on its own, whereas HMR-I can't, or play an auxiliary role. At the HML locus, on the other hand, either HML-E or HML-I alonecan silence the HMLa genes. When ectopically inserted near the MAT locus, HMR-E was shown to be stronger than HML-E. A possible explanation for the difference of the silencers concerning their potencies of silencing is that each silencer consists of a unique sequence, and maybe we will benefit a lot from studying protosilencer.
In addition, there are huge difference between enchromatin and heterchromatin, and converting chromatin form one form to another need its remodeling, but none of the Sir proteins has chromatin remodeling activity. Fortunately, some evidences show that chromatin remodeling proteins Fun30, Snf2, Isw1 are involved in transcriptional silencing, how any of these factors contributes to gene silencing and heterochromatin structure is not known.
Our finding that protsilencer alone can not produce gene silencing; with the help of HML-E silencer, protosilencer Abf1p and ORC binding sites can produce gene silencing on on its both sides while Rap1 binding site only have gene silencing on its right side, these results show that protosilencer play auxiliary role on gene silencing, and Rap1 binding site not only play auxiliary role on gene silencing, but also has boundary acitivity. We also found that increasing the copy number Abf1 binding sites can enhance the role of gene silencing with helping of HML-E silencer, and it is amazing that two copies of the Abf1 binding site alone can have gene silencing without HML-E silencer, but the reasons for the change need further study; we also found that Raplp binding sites varys degrees of gene silencing in different locations, and only has gene silencing effect in its original position, and the possible explanation for the difference maybe because of the sequence around it can increased its role in gene silecing.
In order to study the intrinsic reason of gene silencing of protosilencer, frist we adopted the topology assay to analyze the supericoil chromatin DNA. We found that the ORC binding site and Abf1p binding site together with HML-E silencer formed higher proportion of negative supercoils, but the Rap1 binding site together with HML-E silencer form lower percentage DNA negative supercoils; we also found if we increases the copy number of Abfl binding site which is together with HML-E silencer, negative supercoiled DNA would increase, especially at three copies almost all of DNA circle will be negative supercoils; We found that the Abf1p binding site t with help of HML-E silencer, they would form more negative DNA supercoils at original location of Rap1 binding site than other locations. The DNA supercoils data is consistent with previous analysis of gene silencing.
Moreover, we mapped nucleosomes within HM1-E and protosilencer by micrococcal nuclease digestion and indirect end labeling. The results show that the chromatin nucleosome arrangement between HML-E silencer and ORC binding site or Abfl binding site are similar with HML-E with the HMR-E silencer, but the chromatin nucleosome arrangement between HML-E silencer and Rapl binding site are similar with HML-E alone. In addition, nucleosomes arrangement near the protosilencer in sir- strains is similar with Sir+ strains, so it is indicated that the protosilencer changes nucleosome around it does not depend on the Sir proteins.
In addition, there is evidence implicating chromatin remodeling proteins play an important role on heterochromatin formation, but their exact roles are not clear. We demonstrate that the Fun30p and IswIp chromatin remodeling factors are similarly required for gene silencing at the HML locus, but they differentially contribute to the structure and stability of HML heterochromatin in Saccharomyces cerevisiae. In the absence of Fun30p, only a partially silenced structure is established at HML. This structure likely represents an intermediate state of heterochromatin that is between fully silenced and derepressed chromatin structures. Moreover, Fun30p removal reduces the rate of de novo establishment of heterochromatin, suggesting that Fun30p assists the silencing machinery in forming mature heterochromatin. On the other hand, IswIp is dispensable for the formation of heterochromatin structure, but is instead critically required for maintaining its stability. Therefore, chromatin remodeling proteins may rearrange nucleosomes during the formation of heterochromatin, or serve to stabilize/maintain heterochromatin structure.
为研究原沉默子对基因沉默的作用,本研究采用带有报告基因URA3的不同原沉默子替代HML区域HML-I沉默子,比较URA3的基因表达的差别,发现原沉默子单独情况下没有沉默作用,但与HML-E沉默子共同作用下能在两者之间形成一定的基因沉默；为研究原沉默子拷贝数对基因沉默的影响,本研究利用带有报告基因URA3的不同拷贝数的原沉默子Abflp结合位点替代HML-I沉默子,发现增加拷贝数能增强基因沉默作用；为研究原沉默子在不同位置对基因沉默的影响,本研究利用带有报告基因URA3的原沉默子Raplp结合位点在不同位置的序列替代HML-I沉默子,发现Raplp在本身原来的位置有一定的基因沉默作用,在其他位置基本没有基因沉默作用。为研究原沉默子基因沉默产生差异的原因,通过DNA拓扑结构法研究了不同条件下原沉默子对该区域染色质DNA螺旋程度产生的影响,发现发现负超螺旋DNA的比例Abflp结合位点最高,ORC次之,Rap1结合位点最弱；为研究它们对对染色质结构产生的影响,通过不完全MNase降解结合Southern blot法发现不同的原沉默子与沉默子相互作用下原沉默子附近的核小体结构发生较大变化,但沉默子附近的染色质结构没有发生变化,通过染色质结构变化上不同推测,可能是沉默子与原沉默子之间相互作用会随着它们种类,数目,位置的不同而不同,从而导致形成的基因沉默上存在差别。
为研究重构蛋白在异染色质重排中的具体作用,本研究敲除了酵母的IswIp, Isw2p, Chdlp, Ino80p, Rad54p, Fun30等基因。发现敲除Isw2p, Chdlp, Ino80p, Rad54p基因对酵母的基因沉默没有影响,而敲除IswIp, Fun30基因会酵母的基因沉默产生影响；通过拓扑结构法以及MNase不完全降解结合Southern blot法发现敲除Fun30对异染色质的形成影响很大而对异染色质的维持影响不大,而敲除IswI对异染色质的形成影响不大但对异染色质的稳定维持影响很大。
本研究创新之处：1)不同的原沉默子对插入的外源基因有不同的沉默作用,对异染色质核小体的排列以及染色质DNA螺旋有不同的影响；2)增加原沉默子Abfl结合位点拷贝数能增强基因沉默作用：3)改变原沉默子的排列也会影响基因沉默；4)染色质重构因子Fun30和IswI这两种蛋白对基因沉默起增强作用；5)Fun30对异染色质的形成起重要作用而对异染色质的稳定维持起很小作用,而IswI对异染色质的形成起很小作用,而对异染色质的稳定维持起重要作用。
The basic unit of chromatin is the nucleosome, which is composed of two copies each of the four core histones H2A.H2B, H32. H42 and approximately 146 bp of DNA wrapped in about two turns around a histone octamer complex. Chromatin is divided into different regions, which are loosely structured euchromatin and highly condensed chromatin heterochromatin. Gene expression is normal in euchromatin,but gene expression is silent in heterochromatin which is also known as silent chromatin. Heterochromatin in Saccharomyces cerevisiae exists at HML and HMR loci as well as subtelomeric region. Like its metazoan counterpart, Saccharomyces cerevisiae heterochromatin consists of highly like its metazoan counterpart, its heterochromatin consists of highly ordered and stably positioned nucleosomes. It also bears characteristic histone modifications such as hypoacetylation and hypomethylation, DNA replication occurs in later S phase.
Establishment of HM loci silencing is initiated at silencer, which are composed of two or three combinations of binding sites for proteins Rap1 protein, Abf1 protein, and the ORC. These binding sites are called protosilencer. It was proposed that silencer-binding proteins recruit a complex of SIR complex (Sir2p/Sir3p/Sir4p), which is an integral part of the silent chromatin. Sir2p was found to be a histone deacetylase, Sir3p/Sir4p interact with the N-terminal tails of histones H3 and H4, and there is evidence that Sir3p (hence the SIR complex) has a much higher affinity for hypoaceylated histones. So Sir2p recruited to the silencer deacetylates histones in an adjacent nucleosome enabling it to bind another SIR complex with high affinity, the nucleosome-bound SIR complex in turn deacetylates the neighboring nucleosome allowing it to recruit a new SIR complex,In this manner, the SIR complex promotes its own propagation along the chromatin to form heterochromatin.
Although S. cerevisiae silencers function through a common mechanism, they exhibit different efficiencies in gene silencing. At the HMR locus, HMR-E can silence the HMRa genes on its own, whereas HMR-I can't, or play an auxiliary role. At the HML locus, on the other hand, either HML-E or HML-I alonecan silence the HMLa genes. When ectopically inserted near the MAT locus, HMR-E was shown to be stronger than HML-E. A possible explanation for the difference of the silencers concerning their potencies of silencing is that each silencer consists of a unique sequence, and maybe we will benefit a lot from studying protosilencer.
In addition, there are huge difference between enchromatin and heterchromatin, and converting chromatin form one form to another need its remodeling, but none of the Sir proteins has chromatin remodeling activity. Fortunately, some evidences show that chromatin remodeling proteins Fun30, Snf2, Isw1 are involved in transcriptional silencing, how any of these factors contributes to gene silencing and heterochromatin structure is not known.
Our finding that protsilencer alone can not produce gene silencing; with the help of HML-E silencer, protosilencer Abf1p and ORC binding sites can produce gene silencing on on its both sides while Rap1 binding site only have gene silencing on its right side, these results show that protosilencer play auxiliary role on gene silencing, and Rap1 binding site not only play auxiliary role on gene silencing, but also has boundary acitivity. We also found that increasing the copy number Abf1 binding sites can enhance the role of gene silencing with helping of HML-E silencer, and it is amazing that two copies of the Abf1 binding site alone can have gene silencing without HML-E silencer, but the reasons for the change need further study; we also found that Raplp binding sites varys degrees of gene silencing in different locations, and only has gene silencing effect in its original position, and the possible explanation for the difference maybe because of the sequence around it can increased its role in gene silecing.
In order to study the intrinsic reason of gene silencing of protosilencer, frist we adopted the topology assay to analyze the supericoil chromatin DNA. We found that the ORC binding site and Abf1p binding site together with HML-E silencer formed higher proportion of negative supercoils, but the Rap1 binding site together with HML-E silencer form lower percentage DNA negative supercoils; we also found if we increases the copy number of Abfl binding site which is together with HML-E silencer, negative supercoiled DNA would increase, especially at three copies almost all of DNA circle will be negative supercoils; We found that the Abf1p binding site t with help of HML-E silencer, they would form more negative DNA supercoils at original location of Rap1 binding site than other locations. The DNA supercoils data is consistent with previous analysis of gene silencing.
Moreover, we mapped nucleosomes within HM1-E and protosilencer by micrococcal nuclease digestion and indirect end labeling. The results show that the chromatin nucleosome arrangement between HML-E silencer and ORC binding site or Abfl binding site are similar with HML-E with the HMR-E silencer, but the chromatin nucleosome arrangement between HML-E silencer and Rapl binding site are similar with HML-E alone. In addition, nucleosomes arrangement near the protosilencer in sir- strains is similar with Sir+ strains, so it is indicated that the protosilencer changes nucleosome around it does not depend on the Sir proteins.
In addition, there is evidence implicating chromatin remodeling proteins play an important role on heterochromatin formation, but their exact roles are not clear. We demonstrate that the Fun30p and IswIp chromatin remodeling factors are similarly required for gene silencing at the HML locus, but they differentially contribute to the structure and stability of HML heterochromatin in Saccharomyces cerevisiae. In the absence of Fun30p, only a partially silenced structure is established at HML. This structure likely represents an intermediate state of heterochromatin that is between fully silenced and derepressed chromatin structures. Moreover, Fun30p removal reduces the rate of de novo establishment of heterochromatin, suggesting that Fun30p assists the silencing machinery in forming mature heterochromatin. On the other hand, IswIp is dispensable for the formation of heterochromatin structure, but is instead critically required for maintaining its stability. Therefore, chromatin remodeling proteins may rearrange nucleosomes during the formation of heterochromatin, or serve to stabilize/maintain heterochromatin structure.
引文
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